Colonic drug delivery formulation

ABSTRACT

A delayed release coating comprising a mixture of a first material selected from starch; amylose; amylopectin; chitosan; chondroitin sulfate; cyclodextrin; dextran; pullulan; carrageenan; scleroglucan; chitin; curdulan and levan, and a second material which has a pH threshold at about pH 5 or above, is used to target release of a drug from a core to the intestine, particularly the colon.

The present invention relates to a delayed release formulation with acore comprising a drug and a delayed release coating. In particular, itrelates to a delayed release formulation for a drug for delivering tothe colon.

The targeting of drugs to the colon can be utilised as a means ofachieving local therapy or systemic treatment. The colon is susceptibleto a number of disease states, including inflammatory bowel disease,irritable bowel syndrome, constipation, diarrhoea, infection andcarcinoma. In such conditions, drug targeting to the colon wouldmaximise the therapeutic effectiveness of the treatment. The colon canalso be utilised as a portal for the entry of drugs into the systemiccirculation. Various formulations have been developed for colonic drugdelivery, including pro-drugs as well as formulated dosage forms, withthe latter being more popular since the concept once proved can beapplied to other drugs.

The higher bacterial population in the colon has also been exploited indeveloping colonic drug delivery dosage forms through the use, ascarrier materials, of naturally occurring complex polysaccharides thatconstitute substrates for the numerous enzymes of the resident colonicbacteria. These materials are able to pass through the uppergastrointestinal regions intact but are digested upon entry into thecolon. Those studied so far include amorphous amylose, pectin, chitosanand galactomannan.

Amorphous amylose is resistant to digestion by the enzymes of the uppergastrointestinal tract. It is, however, fermented in the colon byα-amylase enzymes produced by over half of the 400 bacteria speciesresident in the colon.

One major attraction of using polysaccharides in this bacterial enzymeapproach to colonic drug delivery is that materials used are of foodgrade and so would be safe for use in humans. They are usually appliedas coatings or incorporated in the core material as a matrix carrier,and their digestion on entry into the colon by the colonic bacterialenzymes leads to the release of the drug load. An example of such aformulation, which employs an amylose coating, is disclosed inEP-A-0343993 (BTG International Limited).

A major limitation with these naturally occurring materials, however, isthat they swell excessively in aqueous media leading to leaching of thedrug load in the upper gastrointestinal regions. To circumvent thisproblem, they have been utilised in a mixture with impermeable materials(e.g. amorphous amylose mixed with the water-insoluble polymerethylcellulose). However, the problem with such modifications/mixturesis in finding the right balance between hydrophobicity andhydrophilicity that would prevent inopportune drug release in the uppergastrointestinal regions, but which would also at the same time permitenzyme access to the polysaccharide substrate and ensure drug release atan adequate rate in the colon.

An attempt to solve the problem of the excessive swelling of amylose isdisclosed in EP-A-0502032 (British Technology Group Ltd). This employsan outer coating comprising a film forming cellulose or acrylate polymermaterial and amorphous amylose for a tablet comprising an activecompound. One embodiment has the active compound coated first with aninner coating of amylose and then a separate outer coating of thecellulose or acrylate polymer material. Another embodiment has an outercoating which is an admixture of amylose and a cellulose or acrylatepolymer. The reference makes clear that the degradation of the cellulosematerials in vivo is, in general, not pH dependent and it is preferredthat this is also true for the acrylate materials. Every exampledisclosed in the reference is of a pH independent cellulosic or acrylatepolymer.

An article in Journal of Controlled Release (Milojevic et al; 38;(1996); 75-84) reports the results of investigations concerning theincorporation of a range of insoluble polymers into an amylose coatingin order to control amylose swelling. A range of cellulose and acrylatebased co-polymers are assessed, and a commercially available ethylcellulose (Ethocel®) is found to control the swelling most effectively.Another single layer coating that is investigated is a mixture ofamylose and two pH independent acrylic polymers, namely Eudragit® RS andRL, but this coating is found not to give such effective results. A pHdependent soluble coating of Eudragit® L100 is employed but only in amulti-layer system comprising a bioactive coated with an inner coatingof amylose and then an outer coating of Eudragit® L100.

A further amylose-based coating composition is disclosed inWO-A-99/21536 (BTG International Limited). The coating compositioncomprises a mixture of amylose and a water insoluble film-formingpolymer which is formed from a water-insoluble cellulosic or acrylatepolymer material. As with EP-A-0502032, it is made clear thatdegradation of the cellulose materials in vivo is, in general, not pHdependent and it is preferred that this is also true for the acrylatematerials. It would appear that the PCT specification contains atypographical error, because it goes on to say that a preferred form ofacrylate material is “Eudragit L whose degradation is independent ofpH”. It is believed that this should refer to “Eudragit® RL” whosedegradation is indeed independent of pH. It cannot be intended to referto Eudragit® L, as the degradation of this polymer is pH dependent.WO-A-99/25325 (BTG International Limited) also discloses a delayedrelease coating comprising amylose and (preferably) ethyl cellulose oralternatively an acrylate polymer the degradation of which isindependent of pH. The coating composition also includes a plasticiserand the method finds particular application in the preparation of dosageforms comprising active materials that are unstable at temperatures inexcess of 60° C., as the composition is formed at lower temperaturesthan this. It should be noted that this reference also includes thetypographical error relating to Eudragit® L described above.

The Inventors note that the formulations disclosed in the BTG referencesdiscussed above use in the coatings amylose rather than starch and thatrelease from the formulations is sustained along a portion of the gut.

WO-A-03/068196 (Alizyme Theraputics Ltd) discloses a specific delayedrelease coating for the bioactive prednisolone sodium metasulphobenzoatecomprising glassy amylose, ethyl cellulose and dibutyl sebacate.

The use of polysaccharides other than amorphous amylose in a delayedrelease coating is disclosed in GB-A-2367002 (British Sugar PLC).Examples include guar gum, karaya gum, gum tragacanth and xanthan gum.Microparticles of these polysaccharides are dispersed in awater-insoluble film-forming polymer matrix formed for example from acellulose derivative, an acrylic polymer or a lignin.

WO-A-01/76562 (Tampereen Patenttitoimisto Oy) discloses a peroralpharmaceutical formulation containing a drug and a chitosan (apolysaccharide obtained from chitin) for controlling its release. Thedrug and the chitosan are mixed into a homogeneous mechanical powdermixture which is granulated and then optionally tabletised. Thegranulation may be performed with an enteric polymer (such as acoploymer of methacrylic acid) or the granules may be provided with aporous enteric coating.

WO-A-2004/052339 (Salvona LLC) discloses a pH dependent drug releasesystem which is a free-flowing powder of solid hydrophobic nano-spherescomprising a drug encapsulated in a pH-sensitive micro-sphere. Thenano-spheres are formed from the drug in combination with a waxmaterial, and the pH-sensitive micro-sphere formed from a pH-sensitivepolymer (such as a Eudragit® polymer) in combination with awater-sensitive material such as a polysaccharide. The present applicantbelieves however that the very small particle sizes involved in thisreference would not in practice delay the release of the bioactive core,beyond the stomach or duodenum.

An article in the European Journal of Pharmaceutical Sciences (Akhgariet al; 28; Mar. 2006; 307-314) reports the results of investigationsinto the use of certain polymethacrylate polymers to, inter alia,control the swelling of inulin. The polymethacrylate polymers testedwere Eudragit® RS; Eudragit® RL; 1:1 mixtures of Eudragit® RS andEudragit® RL; Eudragit® FS; and 1:1 mixtures of Eudragit® RS andEudragit® S. Results indicated that polymer compositions comprisingsustained release polymethacrylates (Eudragit® RS and Eudragit© RL; pHinsensitive polymers) with inulin displayed swelling profiles indicatinga suitability for use as coatings for colonic release. However, otherresults indicated that polymer compositions comprising inulin witheither Eudragit® FS or 1:1 mixtures of Eudragit® RS and Eudragit® S (pHdependent polymers) would not be suitable for such use due toundesirable swelling profiles.

U.S. Pat. No. 5422121 (Röhm GmbH) discloses an oral dosage formcontaining at least one active ingredient enclosed within a shellmaterial which comprises a polysaccharide that decomposes in the colon.The shell material contains a film-forming polymer in admixture with thepolysaccharide. The ratio by weight of polysaccharide to film formingpolymer is from 1:2 to 5:1, preferably from 1:1 to 4:1. Examples ofsuitable polysaccharides include those polysaccharides that aredecomposable by glycosidic enzymes. Polysaccharides containingconsiderable amounts, preferably about 20 wt % to 100 wt %, of galactoseand mannose units are particularly suitable with locust bean gum andguar gum being preferred. Preferred film-forming polymers includeacrylate polymers that are pH independent (insoluble throughout the GItract) and pH dependent (insoluble in stomach juice but soluble inintestinal juice at pH 5.5 or above). The reference exemplifies the useof a mixture of guar gum with either Eudragit RL 30 D (in a ratio of4:1), Eudragit® L 30 D (in a ratio of 3:1) or Eudragit® S 100 (in aratio of 2.5:1) as a tablet coating.

An article in the European Journal of Pharmaceutical Sciences (Krogarset al; 17; (2002); 23-30) discloses the use of Hylon™ VII (anamylose-rich (˜70 wt %) maize starch; National Starch, Germany) as afilm coating for tablets containing a drug (theophylline). Dissolutionof the tablets in acidic medium was rapid with more than 75% of the drugbeing dissolved within 15 minutes. The coating did not contain a secondfilm forming polymer.

In accordance with a first aspect of the present invention, there isprovided a delayed release drug formulation comprising a particle with acore and a coating for the core, the core comprising a drug and thecoating comprising a mixture of a first material which is susceptible toattack by colonic bacteria and a second material which has a solubilitythreshold at about pH 5 or above, wherein the first material comprises apolysaccharide selected from the group consisting of starch; amylose;amylopectin; chitosan; chondroitin sulfate; cyclodextrin; dextran;pullulan; carrageenan; scleroglucan; chitin; curdulan and levan.

The first material comprises a polysaccharide, preferably containing aplurality of glucose units. Preferably the polysaccharide is starch,amylose or amylopectin, most preferably starch.

It has surprisingly been discovered that the disadvantageous swelling ofmaterials susceptible to attack by colonic bacteria, e.g. amylose, canbe controlled by a pH dependent material which is soluble at pH 5 orabove. In addition, the Inventors have discovered that, unexpectedly,coatings containing large proportions of amylopectin would also work toprovide colonic release of a drug from an oral dosage formulation.

A further technical advantage of the present invention (compared, forexample, to the formulation disclosed in WO-A-01/76562) is thatsubstantially no drug is released for an extended period (that is,whilst the coating is being dissolved), following which the drug isreleased relatively quickly. This is in contrast to homogeneous tabletsfrom which the drug release profile is gradual from the outset ratherthan delayed then pulsatile.

The person skilled in the art is capable of determining whether amaterial is susceptible to attack by colonic bacteria using techniquescomprising part of the common general knowledge. For example, apre-determined amount of a given material could be exposed to an assaycontaining an enzyme from a bacterium found in the colon and the changein weight of the material over time may be measured.

The polysaccharide is preferably starch. Starches are usually extractedfrom natural sources such as cereals; pulses; and tubers. Suitablestarches for use in the present invention are typically food gradestarches and include rice starch; wheat starch; corn (or maize) starch;pea starch; potato starch; sweet potato starch; tapioca starch; sorghumstarch; sago starch; and arrow root starch. The use of maize starch isexemplified below.

Starch is actually a mixture of two different polysaccharides, namelyamylose and amylopectin. Different starches may have differentproportions of these two polysaccharides. Most natural (unmodified)maize starches have from about 20 wt % to about 30 wt % amylose with theremainder being at least substantially made up of amylopectin. Starchessuitable for use in the present invention typically have at least 0.1 wt%, e.g. at least 10% or 15%, preferably at least 35 wt %, amylose. “Highamylose” starches, are starches having at least 50 wt % amylose.Particularly suitable starches have from about 65 wt % to about 75 wt %,e.g. about 70 wt % amylose.

Starches suitable for use in the present invention may have up to 100%amylopectin, more typically from about 0.1 wt % to about 99.9 wt %amylopectin. “Low amylose” starches, i.e. starches having no more than50 wt % amylase and at least 50 wt % amylopectin, e.g. up to 75 wt %amylopectin and even as much as up to 99 wt % amylopectin, are suitable.The starch may be, for instance, unmodified waxy corn starch. Thistypically comprises about 100% amylopectin. “Low amylose” starch was notexpected to be suitable, since low amylose starch is typically degradedby pancreatic enzymes in the small intestine. Preferred starches have nomore than 50 wt % amylopectin. Particularly suitable starches have fromabout 25 wt % to about 35 wt % amylopectin, e.g. about 30 wt %amylopectin.

The person skilled in the art is capable of determining the relativeproportions of amylose and amylopectin in any given starch. For example,near-infrared (“NIR”) spectroscopy could be used to determine theamylose and amylopectin content of a starch using calibration curvesobtained by NIR using laboratory-produced mixtures of known amounts ofthese two components. Further, starch could be hydrolysed to glucoseusing amyloglucosidase. A series of phosphorylation and oxidationreactions catalysed by enzymes result in the formation of reducednicotinamide adenine dinucleotide phosphate (“NADPH”). The quantity ofNADPH formed is stochiometric with the original glucose content.Suitable test kits for this procedure are available (e.g., R-BiopharmGmbH, Germany). Another method that could be used involves subjectingthe coating to digestion by bacterial enzymes, e.g. α-amylase, toproduce short chain fatty acids (“SCFA”) which can be quantified bygas-liquid chromatography using a capillary column.

Preferred starches have amylose in its glassy form although amylase inits amorphous form may also be used in conjunction with the presentinvention.

Preferred starches are “off-the-shelf” starches, i.e. starches whichrequire no processing prior to use in the context of the presentinvention. Examples of particularly suitable “high amylose” starchesinclude Hylon™ VII (National Starch, Germany) or Eurylon™ 7 (Roquette,Lestrem, France) or Amylogel 03003 (Cargill, Minneapolis, USA) all ofwhich are examples of a maize starch having about 70 wt % amylose.

The present invention involves the use of a second material whichdissolves in a pH dependent manner. The second material has a “pHthreshold” which is the pH below which it is insoluble and at or abovewhich it is soluble. The pH of the surrounding medium triggersdissolution of the second material. Thus, none (or essentially none) ofthe second material dissolves below the pH threshold. Once the pH of thesurrounding medium reaches (or exceeds) the pH threshold, the secondmaterial becomes soluble. By “insoluble” we mean that 1 g of the secondmaterial requires more than 10,000 ml of solvent (surrounding medium) todissolve at a given pH. By “soluble”, we mean that 1 g of the secondmaterial requires less than 10,000 ml, preferably less than 5,000 ml,more preferably less than 1000 ml, even more preferably less than 100 mlor 10 ml of solvent to dissolve at a given pH. Surrounding mediumpreferably means the medium in the gastro intestinal tract, such as thegastric juice or intestinal juice. Alternatively, the surrounding mediummay be in the vitro equivalent of the medium in the gastrointestinaltract.

The normal pH of gastric juice is usually in the range of 1 to 3. Thesecond material is insoluble below pH 5 and soluble at about pH 5 orabove and soluble at about pH 5 or above and, thus, is usually insolublein gastric juice. Such a material may be referred to as an “enteric”material.

The second material is soluble at pH 5 or above, e.g. in intestinaljuice. The pH of intestinal juice gradually increases from about 6 inthe duodenum to about 7 to 8 in the colon. The second material ispreferably insoluble below pH 6.5 (and soluble at about pH 6.5 or above)and, more preferably, is insoluble below pH 7 (and soluble at about pH 7or above).

The pH threshold at which a material becomes soluble may be determinedby a simple titration technique which would be part of the commongeneral knowledge to the person skilled in the art.

The second material is typically a film-forming polymeric material suchas an acrylate polymer, a cellulose polymer or a polyvinyl-basedpolymer. Examples of suitable cellulose polymers include celluloseacetate phthalate. (“CAP”); cellulose acetate trimellitate (“CAT”); andhydropropylmethylcellulose acetate succinate. Examples of suitablepolyvinyl-based polymers include polyvinyl acetate phthalate (“PVAP”).

The second material is preferably a co-polymer of a (meth)acrylic acidand a (meth)acrylic acid C₁₋₄ alkyl ester, for instance, a copolymer ofmethacrylic acid and methacrylic acid methyl ester. Such a polymer isknown as a poly(methacrylic acid/methyl methacrylate) co-polymer.Suitable examples of such co-polymers are usually anionic and notsustained release polymethacrylates. The ratio of carboxylic acid groupsto methyl ester groups (the “acid:ester ratio”) in these co-polymersdetermines the pH at which the co-polymer is soluble. The acid:esterratio may be from about 2:1 to about 1:3, e.g. about 1:1 or, preferably,about 1:2. The molecular weight (“MW”) of preferred anionic co-polymersis usually from about 120,000 to 150,000, preferably about 135,000.

Preferred anionic poly(methacrylic acid/methyl methacrylate) co-polymersinclude Eudragit® L (acid:ester ratio about 1:1; MW about 135,000; pHthreshold of about 6.0); Eudragit® S (acid:ester ratio about 1:2; MWabout 135,000; pH threshold of about 7); and Eudragit® FS (a poly(methylacrylate/methyl methacrylate/methacrylic acid; acid:ester ratio of about1:10; MW about 220,000; pH threshold of about 7.)

The second material may be a copolymer of methacrylic acid and ethylacrylate. Eudragit® L100-55 poly(methacrylic acid/ethyl acrylate);acid:ester ratio of about 1:1; MW about 250,000; pH threshold of about5.5 is suitable. The Eudragit® co-polymers are manufactured and/ordistributed by Degussa AG, Darmstadt, Germany.

Mixtures of film forming polymer materials may be used as appropriate.An example of a suitable mixture would include a mixture, e.g. a 1:1mixture, of Eudragit® L and Eudragit S. However, the use of a particularfilm forming polymer material, e.g. a poly(methacrylic acid/methylmethacrylate) co-polymer, alone is preferred.

The use of Eudragit® S alone as the second material is particularlypreferred.

In a preferred embodiment, it has been found that a mixture of twosuitable polymers at an appropriate ratio, applied as a film coating onto a core, at least minimises, and can substantially eliminate, drugrelease in the stomach and small intestine. Subsequent drug release inthe colon is believed to occur by the combined active physiologicaltriggers: i.e. by dissolution of the second material, particularlyEudragit® S, and digestion of the first material, e.g. starch oramylose.

The proportion of the first material to the second material is typicallyless than 99:1 and may in some circumstances be up to 50:50. Theproportion is usually up to 35:65 and is preferably from 15:85 to 35:65,e.g. 15:85 to 30:70. The Inventor has discovered that a ratio of firstmaterial to second material from about 25:75 to about 35:65, e.g. about30:70, is particularly suitable for targeting release of the drug to thecolon, particularly if the first material is starch and the secondmaterial is Eudragit® S. The mixture of first and second materials ispreferably substantially homogenous.

Optionally, conventional excipients such as plasticisers for filmformation (for example, triethyl citrate) and anti-tack agents (such asglyceryl monostearate) may be included in amounts up to 30 % by weightof the final composition of the polymer coating preparation.

The thickness of the coating of the particle is typically from about 10μm to about 150 μm. The thickness of a specific coating will, however,depend on the composition of the coating. For example, coating thicknessis directly proportional to the amount of polysaccharide in the coating.

Thus, in embodiments where the coating comprises high amylose starch andEudragit™ S at a ratio of about 30:70, the coating thickness may be fromabout 70 μm to about 130 μm, and preferably from about 90 μm to about110 μm. The thickness (in μm) for a given coating composition isindependent of core size.

The thickness of the coating may also be measured by the “theoreticalweight gain” (“TWG”) of the coated formulation. The TWG for the presentformulation will depend on a number of factors including the compositionof the coating and the size of the core to be coated. For example, inembodiments where the core is a small tablet (e.g. having a diameter ofabout 8 mm) and the coating comprises high amylose starch and Eudragit™S (e.g. in a ratio of about 30:70), the TWG is typically from about 4%to about 12%, e.g. from about 5% to about 10%, preferably from about 8%to about 9%. In embodiments where the core is a pellet (e.g. having adiameter of about 1 mm) having the same coating, the TWG may be fromabout 15% to about 35%, e.g. from about 20% to about 30%, preferablyabout 25%.

By saying that the coating comprises a mixture of the first and secondmaterials, it is intended to exclude the known multi-layer dosage form(disclosed for example in Milojevic et al. described above) in which anactive core is coated first with an inner coating of amylose and thenwith an outer coating of Eudragit® L100. In the context of the presentinvention, such a multi-layer dosage form does not comprise a mixture ofstarch and Eudragit® L100. The coating is preferably a single layer of amixture of the first and second materials, preferably a homogenousmixture.

The formulation of the present invention may however have an additionallayer either between the active core and the layer comprising thedelayed release composition of the present invention and/or an outerlayer coating the delayed release composition layer of the presentinvention. For example, if the delayed release composition layercomprises a mixture of Eudragit® L and starch, the addition of an outerlayer of a pH dependent release coating material having a pH thresholdof about 7, e.g. Eudragit® S, may be preferable. In preferredembodiments, the delayed release coating of the present invention isapplied directly to the active core, i.e. there is no additional layerbetween this coating and the active core. The delayed release coating ofthe present invention is preferably the outer coating of theformulation. Advantageously, it has been found that no additional outerlayer is required to ensure that the composition is a delayed releasecomposition.

The composition preferably forms a coating around the bioactive which ismost preferably mixture of starch and Eudragit® S. The “bioactive” isusually the core comprising the drug.

The formulation comprises at least one particle with a core and acoating for the core. The formulation may comprise any suitable coatedoral dosage form including capsules; tablets; mini-tablets; pellets;granules; and crystals.

The minimum diameter of each particle is typically at least about 10⁻⁴m,usually at least about 5×10⁻⁴m and, preferably, at least about 10⁻³m.The maximum diameter is usually no more than 30 mm, typically no morethan 20 mm and, preferably, no more than 10 mm. In preferredembodiments, the particle has a diameter from about 0.2 mm to about 15mm, preferably from about 1 mm to about 4 mm (e.g. for pellets ormini-tablets) or from about 6 mm to about 12 mm (e.g. for certaintablets or capsules). The term “diameter” refers to the largest lineardimension through the particle.

The formulation may comprise a plurality of particles in order toprovide a single dose of the drug(s), particularly in embodiments inwhich the particle is “small”, e.g. having a diameter of less than 5 mm.Multi unit dosage forms comprising particles having a diameter of lessthan 3 mm are preferred.

The present invention has application in a multi-phasic drug releaseformulation comprising at least two pluralities of particles, e.g.coated pellets, in the same dosage form, e.g. a capsule, in which theparticles of one plurality are differentiated from the particles of theor each other plurality by the coating. The coatings may differ from oneplurality to the next in terms of coating thickness or composition, e.g.the ratio and/or identity of components. Multi-phasic drug releaseformulations would be particularly suitable for suffers of Crohn'sdisease affecting different regions along the intestine.

The “core” is usually a single solid body. The core may consist of thedrug(s) alone or may be a bead of edible material, e.g. sugar, which iscoated with a layer comprising the drug(s). More usually, however, thecore consists of a mixture of the drug(s) with a filler or diluentmaterial, e.g. lactose or cellulose material such as microcrystallinecellulose; a binder, e.g. polyvinylpyrrolidone (“PVP”); a disintegrant,e.g. Ac-Di-Sol™ (i.e. croscarmellose sodium); and/or a lubricant, e.gmagnesium stearate. The core may be a compressed granulate comprising atleast some of these materials.

Release from formulations according to the present invention is delayeduntil the intestine and preferably the colon. Release from certainformulations may also be sustained. However, in preferred formulations,release is pulsatile.

A formulation is usually defined as gastric resistant if there is lessthan 10 wt % drug release in acidic media after 2 hours. Formulationsaccording to the present invention typically display far less than 10 wt% drug release in acidic media and may be considered to be gastricresistant. The formulations usually display less than 1 wt % drugrelease in acidic media and, typically, display substantially no drugrelease in acidic media. When starch is combined with an acrylate filmforming material to form the coating for the core, typically less than5% drug release occurs over 5 hours in conditions simulating the stomachand small intestine. On combination of starch with a cellulosic filmforming material for the coating for the core, typically less than 10%drug release occurs over 5 hours in conditions simulating the stomachand small intestine.

The time between initial exposure to conditions suitable for drugrelease and the start of drug release is known as the “lag time”. The“lag time” depends on a number of factors including coating thicknessand composition. Formulations according to the present invention usuallydisplay a lag time in colonic conditions of at least 30 minutes. In mostembodiments of the present invention, the lag time is from about 30minutes to about 3 hours and, in preferred formulations, the lag time ispreferably from about 45 minutes to about 2 hours.

The time between initial exposure to conditions suitable for drugrelease and complete drug release also depends on a number of factorsincluding coating composition and the nature of the drug. In mostembodiments of the present invention, this time is usually no more than5 hours. In preferred embodiments, this time is usually no more than 4hours.

By way of an example, in embodiments in which a tablet core is coated toa thickness of from 8% to 9% TWG with a coating comprises a high amylosestarch and Eudragit S (30:70), the time between initial release andcomplete release may be less than about 2 hours, preferably less thanabout 1.5 hours.

In a preferred embodiment, the core is a pellet having a diameter ofabout 1 mm. In another embodiment, the core is a tablet having adiameter of about 8 mm. In both cases, the coating is preferably a 30:70mixture of high amylose starch, e.g. Eurylon™ 7, and an acrylic polymer,e.g. Eudragit™ S. In both preferred embodiments, the core is coated to athickness of about 100 μm which is from about 8% to about 9% TWG for thetablet and from about 27% to about 32 wt % for the pellet.

According to a second aspect of the present invention, there is provideda formulation according to the first aspect for use in a method ofmedical treatment of the human or animal body by therapy.

The core comprises at least one drug. The formulation is usually used toadminister a single drug as the sole therapeutically active component.However, more than one drug may be administered in a single formulation.

The formulation of the present invention is designed to administer awide range of drugs. Suitable drugs include those drugs which are knownfor intestinal administration using known delayed release oralformulations. The present invention may be used to administer drugshaving a local or a systemic effect.

The formulation of the present invention has particular application inthe intestinal administration of a drug comprising at least one acidicgroup such as a carboxylic acid group. Such drugs may be acidic drugs orzwitterionic drugs. An example of such a drug is 5-aminosalicylic acid(“5-ASA”).

The identity of the drug(s) in the formulation obviously depends on thecondition to be treated. In this connection, the formulation hasparticular application in the treatment of IBD (including Crohn'sdisease and ulcerative colitis); IBS; constipation; diarrhoea;infection; and carcinoma, particularly colon or colorectal cancer).

For the treatment or prevention of IBD, the formulation may comprise atleast one drug selected from the group consisting of anti-inflammatoryagents (e.g. 5-ASA); steroids (e.g. prednisolone; budesonide orfluticasone); immunosuppressants (e.g. azathioprine; cyclosporin; andmethotrexate); and antibiotics.

For the treatment or prevention of cancer, the formulation may compriseat least one antineoplastic agent. Suitable antineoplastic agentsinclude fluorouracil; methotrexate; dactinomycin; bleomycin; etoposide;taxol; vincristine; doxorubicin; cisplatin; daunorubicin; VP-16;raltitrexed; oxaliplatin; and pharmacologically acceptable derivativesand salts thereof. For the prevention of colon cancer or colorectalcancer, primarily in patients suffering from colitis, the formulationmay comprise the anti-inflammatory agent, 5-ASA.

For the treatment or prevention of IBS, constipation, diarrhoea orinfection, the formulation may comprise at least one active agentsuitable for the treatment or prevention of these conditions.

Pharmacologically acceptable derivatives and/or salts of the drugs mayalso be used in the formulation. An example of a suitable salt ofprednisolone is methyl prednisolone sodium succinate. A further exampleis fluticasone propionate.

The present invention has particular application in either the treatmentof IBD (particularly, ulcerative colitis) or the prevention of coloncancer or colorectal cancer (primarily in colitis patients), both using5-ASA. It also has application as a portal of entry of drugs into thesystemic circulation via the colon. This is particularly advantageousfor peptide and protein drugs which are unstable in the uppergastrointestinal tract. The present invention may also be utilised forthe purpose of chronotherapy.

In a third aspect of the invention, there is provided a method oftargeting a drug to the colon comprising administering to a patient aformulation as defined above.

In a fourth aspect of the invention, there is provided the use of aformulation as defined above in the manufacture of a medicament for thetreatment or prevention of IBD (particularly ulcerative colitis); IBS;constipation; diarrhoea; infection; and cancer.

There is also provided the use of at least one drug selected fromanti-inflammatory agents and steroids in the manufacture of a medicamentcomprising a formulation as defined above for use in the treatment ofIBD. In addition, there is also provided the use of at least oneantineoplastic agent in the manufacture of a medicament comprising aformulation as defined above for use in the treatment of carcinoma.Further, there is also provided use of 5-ASA in the manufacture of amedicament comprising a formulation as defined above for use in theprevention of colon cancer or colorectal cancer.

According to a fifth aspect of the present invention, there is provideda method of medical treatment or prevention of IBD or carcinomacomprises administering to a patient a therapeutic amount of aformulation as defined above.

The formulation will typically comprise a therapeutically effectiveamount of the or each drug which may be from about 0.01 wt % to about 99wt %, based on the total weight of the formulation. The actual dosagewould be determined by the skilled person using his common generalknowledge. However, by way of example, “low” dose formulations typicallycomprise no more than about 20 wt % of the drug, and preferably comprisefrom about 1 wt % to about 10 wt %, e.g. about 5 wt %, of the drug.“High” dose formulations typically comprise at least 40 wt % of thedrug, and preferably from about 45 wt % to about 85 wt %, e.g. about 50wt % or about 80 wt %.

According to a sixth aspect of the present invention, there is provideda method of preparing a delayed release drug formulation according tothe first aspect, said method comprising:

forming a core comprising at least one drug; and

coating the core with a polymer coating preparation comprising a mixtureof a first material which is susceptible to attack by colonic bacteriaand a second material which has a pH threshold at about pH 5 or above,

wherein the first material comprises a polysaccharide selected from thegroup consisting of starch; amylose; amylopectin; chitosan; chondroitinsulfate; cyclodextrin; dextran; pullulan; carrageenan; scleroglucan;chitin; curdulan and levan. Preferred polysaccharides are as detailedabove. The core is preferably spray coated with said polymer coatingpreparation.

In embodiments in which the core is formed from a compressed granulate,the method preferably comprises:

dry mixing the drug(s) with at least one excipient to form a drymixture;

wet granulating at least a portion of said dry mixture to form a wetgranulate;

compressing at least a portion of said wet granulate to form said core;and

spray coating said core with said polymer coating preparation to formsaid delayed release drug formulation. A fluidised bed spray coatingmachine is preferably used to coat the core(s) with the polymer coatingpreparation to form the particle(s) of the formulation.

In preferred embodiments, the method comprises:

forming an aqueous dispersion comprising said first material;

forming an alcoholic or aqueous solution comprising said secondmaterial; and

adding, preferably drop-wise, at least a portion of said aqueousdispersion of said first material to at least a portion of saidalcoholic or aqueous solution of said second material to form saidpolymer coating preparation.

The first material is usually dispersed in at least one alcohol,preferably a C₁ to C₆ alcohol, e.g. methanol; ethanol; propan-1-ol;propan-2-ol; butan-1-ol; butan-2-ol; and mixtures thereof, particularlybutan-1-ol alone, and then water is usually added subsequently with goodagitation. The resulting aqueous dispersion is usually heated to boilingand then cooled with stirring overnight. The purpose of the alcohol(s)is to solvate the first material ready to form the aqueous dispersion.Alternatively, the material can be dispersed directly in water.

The second material is typically dissolved in at least one solvent, forinstance water or an organic solvent. The organic solvent may be analcohol, e.g. methanol; ethanol; propan-2-ol; methyl glycol; butylglycol; acetone; methyl glycol acetate; and mixtures thereof such asacetone and isopropyl alcohol (e.g. in a ratio of about 4:6). The secondmaterial is preferably dissolved in ethanol (preferably from 85 to 98%),under high speed stirring.

The polymer coating preparation is preferably formed by adding anappropriate quantity of the aqueous dispersion to the alcoholicsolution, drop-wise under fast stirring. The further excipient(s) suchas a plasticiser (e.g. triethyl citrate) and/or a lubricant (e.g.glyceryl monostearate) is usually added to the preparation whilestirring.

A number of preferred embodiments of the present invention will now bedescribed with reference to the drawings, in which:—

FIG. 1 is a graph depicting the dissolution profiles of mixed filmcoated prednisolone tablets at 5% TWG and Eudragit® S coated tablets at5% TWG in pH 7.0 buffer;

FIG. 2 is a graph depicting the dissolution profiles of mixed filmcoated tablets as for FIG. 1 but with 6% TWG;

FIG. 3 is a graph depicting the dissolution profiles of mixed filmcoated tablets as for FIG. 1 but with 7.4% TWG;

FIG. 4 is a graph depicting the dissolution profiles of mixed filmcoated tablets as for FIG. 1 but with 8.3% TWG;

FIG. 5 is a graph depicting the dissolution profiles of prednisolonetablets coated with 30% starch:70% Eudragit® S at various polymer weightgains and Eudragit® S coated tablets at 5% TWG;

FIG. 6 is a graph depicting the dissolution profile of prednisolonetablets coated with 30% starch:70% Eudragit® S in pH 6.8 buffer, withand without pancreatin;

FIG. 7 is a graph depicting drug release from prednisolone tabletscoated to 8.3% TWG in pH 6.8 buffer containing 50 U/ml amylase;

FIG. 8 is a graph depicting the dissolution profile of 5-ASA tabletscoated with 30% starch:70% Eudragit® S to 8.3% TWG in pH 6.8 buffer;

FIG. 9 is a graph depicting the dissolution profiles of 5-ASA tabletscoated with 30% starch:70% Eudragit® S to various polymer weight gainsin pH 6.8 buffer containing 50 U/ml amylase;

FIG. 10 is a graph depicting the dissolution profiles of prednisolonetablets coated with 70% Eudragit® S:30 wt % starch having either 70 wt %or 27 wt % amylose in pH 7 buffer;

FIG. 11 is a graph depicting the dissolution profiles of prednisolonetablets as for FIG. 10 in pH 6.8 buffer;

FIG. 12 is a graph depicting the dissolution profiles of theprednisolone tablets as for FIG. 10 in pH 6.8 buffer containing 50 U/mlamylase;

FIG. 13 is a graph depicting the dissolution profile of prednisolonetablets coated with 70% Eudragit® L:30% starch to 8.3% TWG in pH 5.5buffer; FIG. 14 is a graph depicting the dissolution profile ofprednisolone tablets as for FIG. 13 in pH 5.5 buffer containing 50 U/mlamylase;

FIG. 15 is a graph depicting the dissolution profile of prednisolonetablets coated with 70% HPMCAS-HG:30% starch in pH 6.5 buffer;

FIG. 16 is a graph depicting the dissolution profile of the prednisolonetablets as for FIG. 15 in pH 6.5 buffer containing 50 U/ml amylase; and

FIG. 17 is a graph depicting the dissolution profile of the prednisolonetablets as for FIG. 15 in pH 6.8 buffer.

EXAMPLE 1 Preparation of Prednisolone Tablets

Prednisolone tablets (weight 200 mg, diameter 8 mm and standardbi-concave) were prepared according to the following formula:

Lactose 85%  Prednisolone 5% PVP 5% Ac-Di-Sol ™ 4% (⅔ intragranular and⅓ extragranular Magnesium stearate 1% (extragranular)

Prednisolone was dry mixed with the excipients and then wet granulated.Granules of 500-710 [mu]m size fraction were compressed using a singlepunch tabletting machine (Manesty, UK).

Formulation for Starch Aqueous Dispersion

Eurylon ™ 7 16 g Butan-1-ol 32 g Water 352 g 

Eurylon™ 7 starch was dispersed well in the butan-1-ol and watersubsequently added with good agitation. The resulting dispersion wasthen heated to boiling, and cooled with stirring overnight. The % solidscontent of the cooled dispersion was calculated based on the finalweight of the dispersion (allowing for evaporation during heating).

Formulation for Eudragit® S Solution

Eudragit® S solution was prepared by dissolution of Eudragit® S 100polymer in 96% ethanol under high speed stirring. The final solutioncontained approximately 6% polymer solids.

Mixed Starch-Eudragit® Coating Dispersion

Appropriate quantities of the starch dispersion and Eudragit® solutionwere mixed to give the required ratios stated as the dry polymersubstance. The starch was always added to the Eudragit® solutiondrop-wise under fast stirring. The resulting dispersions were leftstirring for two hours before the addition of the excipients and foranother two hours after adding excipients. The added excipients were:

Triethyl citrate 10% of dry polymer substance Glyceryl Monostearate 5%of dry polymer substance

The final mixed polymer coating preparation was film coated onto thetablets using a fluidised bed spray coating machine. Coating thicknesswas estimated as % weight increase of the tablets following coating (%TWG)

The spray coating parameters were as follows:

Flow rate 0.7 ml/minute Atomising pressure 0.2 bar Coating temperature40° C.

In Vitro Tests

Starch dispersion was prepared from Eurylon 7, a “high amylose” starch,and mixed with a solution of Eudragit® S in ethanol. The composition andpreparation method for the coating dispersions are as described above.Various starch/Eudragit® S combinations were prepared containing 15%,20%, 25%, 30% and 35% starch. The mixed Eudragit®/starch coatingdispersions were then film coated onto prednisolone tablets preparedaccording to the method described above. Tablets were coated to varyingthicknesses, calculated as total weight gain on the polymer, to alsodetermine the optimum coating thickness. The coating mixture yieldedgood quality films up to a ratio of 30% starch.

Coated tablets were then tested in vitro for drug release in varying pHbuffer solution. The optimum starch/Eudragit® S ratio and coating weightgain was primarily based on comparison

of the dissolution profile with conventional Eudragit® S coated tablets.

-   Results are shown in FIGS. 1-7.

Very surprisingly, these mixed film coated tablets were able to resistdrug release in pH 1.2 HCl simulating the gastric media (see theleft-hand side of the graphs of FIGS. 1-6).

There was also no drug release from any of the coated tablets for up to12 hours in pH 6.8 simulating the small intestinal media (see FIG. 6).Previous in vitro studies using mixed amylose/acrylate polymers based onthe water-insoluble Eudragit® RL and RS products showed uncontrollableswelling and rapid drug release in acid and buffer (Milojevic et al.,1996).

Drug release profiles from the coated tablets in pH 7.0 buffer media areshown in FIGS. 1 to 5. Based on an analysis of the dissolution profiles,tablets coated with a 30% starch/Eudragit® mixture to a film thicknessequivalent to a TWG of 8.3% was judged to be optimal, and were furthertested to assess the digestibility of the starch component of the film.

The tablets were dissolution tested in pH 6.8 buffer containing 50 U(units)/ml α-amylase derived from B. licheniformis (see FIG. 7). Adissolution test was also carried out in pH 6.8 media with pancreatin totest whether the starch is digestible by pancreatic α-amylase (see FIG.6).

Results of the dissolution tests in the presence of the enzymes showthat the starch component of the film is indigestible in the presence ofthe pancreatin (suggesting resistance in the small intestine), but drugrelease occurred within three hours in the presence of α-amylase from B.licheniformis. These results provide evidence that the mixed filmresists drug release in simulated conditions of the uppergastrointestinal tract but is digestible in the presence of bacterialenzymes (even at a pH lower than the threshold pH of the Eudragit® Spolymer for dissolution)

In Vivo Study in Healthy Volunteers

Following the surprising success of the in vitro studies with the mixedstarch/Eudragit® S film coated tablets; the performance of the dosageform was tested in healthy human subjects. The tablets wereradio-labelled with Indium-111 and administered to eight healthy malevolunteers on three separate occasions. The transit and disintegrationsite of the tablet in the gastrointestinal tract was followed using agamma camera.

The time and site of disintegration of these mixed film tablets can beseen in Table 1. The results show surprisingly excellent colonictargeting, with tablet disintegration occurring primarily in the colon.

The results from the healthy volunteer study provides evidence thatstarch and Eudragit® mixed at a proportion of 30% starch to 70%Eudragit® S and coated onto tablets at approximately 8.3% TWG, is ableto resist tablet disintegration in the stomach and small intestine buttrigger disintegration in the colon.

Table 1 shows the site and time of disintegration of 30% starch and 70%Eudragit® S coated tablets in eight healthy male volunteers on threeseparate occasions.

Key to Table 1:

-   “Fasted”—tablet given on an empty stomach;-   “Pre-fed”—tablet given on an empty stomach, but meal administration    30 minutes post dose; and-   “Fed”—tablet given after breakfast.-   “ICJ”—ileocolonic junction;-   “AC”—ascending colon;-   “HF”—hepatic flexure; and-   “SF”—splenic flexure.

TABLE 1 Treatment 1 Treatment 2 Treatment 3 (Fasted) (Pre-fed) (Fed)Subject Site Time Site Time Site Time 1 ICJ 237 ICJ 244 AC 240 2 AC 200ICJ 339 AC 316 3 AC 201 ICJ 350 AC 510 4 AC 292 HF 390 AC 415 5 TC 465SF 678 AC 555 6 Subject did — AC 523 AC 523 not attend study day 7 AC274 AC 244 SF 465 8 AC 614 Tablet did not — AC 455 empty from stomach

EXAMPLE 2

Tablets (weight 200 mg; diameter 8 mm; standard bi-concave) containing 5wt % 5-aminosalicylic acid in place of 5 wt % prednisolone were preparedand coated with a polymer mixture comprising 70% Eudragit® S:30% starch(Eurylon™ 7) to 5%, 6%, 7% and 8.3% TWG in accordance with the proceduregiven in Example 1.

The 5-ASA tablets with different weight gains of 5,6, 7 and 8.3% werethen tested in vitro for drug release in pH 6.8 buffer in the absence ofα-amylase. FIG. 8 indicates that for the 5-ASA tablet coated to 8.3% TWGthere was no release of 5-ASA for about 9 hours with almost completerelease after about 11 hours.

The 5-ASA tablets with each of the different TWGs were then tested invitro for drug release in the presence of 50 U/ml α-amylase. FIG. 9indicates that drug release was much faster for all TWGs in the presenceof α-amylase.

The 5-ASA tablet coated to 7% TWG gave a similar lag-time in pH 6.8buffer (about 2 hours) as a 5 wt % prednisolone tablet coated to 8.3%TWG. Without wishing to be bound by any particular theory, this resultmay be explained by 5-ASA exhibiting acidic properties as it dissolvesin the near neutral buffer, thus reducing the pH at the tabletcore/polymer boundary layer relative to the bulk medium and consequentlyretarding dissolution of the polymer coating.

EXAMPLE 3

Tablets (weight 200 mg; diameter 8 mm; standard bi-concave) containing 5wt % prednisolone were prepared and coated with a polymer mixturecomprising 70% Eudragit® S:30% starch to 8.3% TWG in accordance with theprocedure given in Example 1. The starch used was either a “high”amylose maize starch (Eurylon™ 7; ˜70 wt % amylose) or a “low” amylosestarch (natural maize starch; ˜27 wt % amylose; Sigma, Poole, UK).

The tablets were then tested in vitro for drug release in pH 7 bufferwithout amylase and then in pH 6.8 buffer, with and without 50 U/mlα-amylase.

FIGS. 10 and 11 indicate that drug release is quicker using “low”amylose starch. FIG. 11 indicates that there is a lag-time of about 2.5hours in small intestinal conditions for the “low” amylose starchtablets which was shorter than the lag time for the “high” amylosestarch tablets. This result may be explained by noting that amylopectinis more water soluble than amylose. Thus, the greater the proportion ofamylopectin, the quicker the coating dissolves in aqueous solution. FIG.12 indicates that drug release is substantially quicker in the presenceof α-amylase.

The tablets having the coating containing “low” amylose starch have alsobeen demonstrated (using the same procedure as for FIG. 6) to beindigestible to pancreatin for several hours, further substantiating theresistance of the “low” amylose system in the small intestine. Suchresistance is surprising as amylopectin is a substrate of pancreaticamylase (present in pancreatin) and, therefore, digestion of the coatingand drug release would have been expected.

EXAMPLE 4

Tablets (weight 200 mg; diameter 8 mm; standard bi-concave) containing 5wt % prednisolone were prepared and coated with a polymer mixturecomprising 70% Eudragit® L:30% starch (Eurylon™ 7) to 8.3% TWG inaccordance with the procedure given in Example 1.

The tablets were then tested in vitro for drug release in pH 5.5 buffer,first without amylase and then with 50 U/ml α-amylase.

FIG. 13 indicates a lag time of just under 4 hours in small intestinalconditions. However, in the presence of α-amylase, the lag-time wasabout 3 hours (FIG. 14). The results indicate that this coating systemcould be used for drug release in the proximal small intestine.

EXAMPLE 5

Tablets (weight 200 mg; diameter 8 mm; standard bi-concave) containing 5wt % prednisolone were prepared and coated with a polymer mixturecomprising 70% hydroxypropyl methylcellulose acetate succinate(“HPMCAS”):30% starch (Eurylon™ 7) to 8.3% TWG generally in accordancewith the procedure given in Example 1. The HPMCAS (ShinEtsu, Japan) usedhad the granular grade HG with a pH threshold of 6.8. The HPMCAS-HG wasdissolved in 90% ethanol and the aqueous dispersion of starch added toit.

The tablets were then tested in vitro for drug release in pH 6.5 buffer,first without amylase and then with 50 U/ml α-amylase. Further tabletswere then tested in vitro for drug release in pH 6.8 buffer in theabsence of α-amylase.

FIG. 15 indicates that the coating had a tendency to swell below the pHthreshold of the HMPCAS-HG, allowing slow diffusion of the drug out ofthe formulation prior to dissolution of the coating and a burst of drugrelease. The lag-time prior to the onset of diffusion in pH 6.5 bufferin the absence of α-amylase was about 2 hours which would be sufficientto retard release until the distal small intestine. Diffusion continuedfor approximately an additional 4.5 hours resulting in almost 40% of thedrug diffusing out prior to the burst release.

In the presence of α-amylase, there was no lag time in pH 6.5 bufferwith diffusion starting immediately and releasing 20% of the drug priorto the onset of the burst release (FIG. 16). However, at pH 6.8, thisdiffusion phenomenon does not exist, presumably due to the fasterdissolution of the system (FIG. 17).

It will be appreciated that the invention is not restricted to thedetails described above with reference to the preferred embodiments butthat numerous modifications and variations can be made without departingfrom the spirit or scope of the invention as defined by the followingclaims.

1. A delayed release drug formulation comprising a particle with a core and a coating for the core, the core comprising a drug and the coating comprising a mixture of a first material which is susceptible to attack by colonic bacteria and a second material which has a pH threshold at about pH 5 or above, wherein the first material comprises a polysaccharide selected from the group consisting of starch; amylose; amylopectin; chitosan; chondroitin sulfate; cyclodextrin; dextran; pullulan; carrageenan; scleroglucan; chitin; curdulan and levan. 